The SARS disease originated from the Guangdong Province of southern China where a farmer first showed the symptoms of SARS in 2002 but was not diagnosed definitively in the hospital. This viral disease did not get diagnosed until 2003 when a physician had a patient that traveled from Guangdong Province, Hong Kong, and Hanoi Vietnam. He and the patient died from the illness soon after [3]. The infected individuals came in contact with other people, which mitigated the spread of the disease to about thirty-seven countries in total, mostly in Asian countries such as Taiwan, Philippines, and Vietnam, but also in North America and some European countries. These cases were proven to have come from individuals who flew in from China, Hong Kong, or other countries where the disease was present.
The death toll of SARS was greater with adults the age of 65 and over most likely due to their lowered immune system. It has numerous symptoms, mainly known to be coughing, difficulty breathing, greater than 100.4-degree Fahrenheit fever, and other respiratory problems. The more common symptoms resemble that of the flu:
chills
fever
headache
muscle ache.
Most patients also developed pneumonia after one week of infection [6]. Although not often, there are known to have been symptoms of diarrhea, nausea, vomiting, and sore throat that come up in some cases. The more severe instances have led patients to respiratory, liver and even heart failure [3].
Reported cases of SARS have decreased greatly after the 2003 pandemic mainly because of the intense screening and protocols taken to contain its spread. Tests and planned treatments are available with the small number of cases that have risen these past decade. Even though SARS has infected less and less people in the past few years, an outbreak is still possible in the future, so preparation and prevention are still being done to this day.
Fig 1. SARS coronavirus stained for viewing. The spikes surrounding it is similar to a crown, hence the name coronavirus [3].
TARGET INFORMATION:
There is no specific treatment or vaccine for the SARS virus, but studies have shown that the virus attaches to a receptor on the cell called angiotensin-converting enzyme 2 (ACE-2). This receptor is expressed mainly in the heart, kidneys, lungs, and gastrointestinal tract, which also happens to be where the SARS-CoV is found in infected patients. ACE-2 is a type I transmembrane glycoprotein made up of 805 amino acids [2]. Its molecular weight is unknown.
ACE-2 is a multifactorial enzyme that is known to be a protective component of the major organs in the body. In a normal cell, ACE-2 is a counter-regulator of its carboxylase homolog ACE, which increases blood pressure by constricting blood vessels. It also serves as an absorber of amino acids in the kidney and gut. At the same time, it is known to increase the effects and presence of the SARS-CoV by tenfold [2].
Fig 2. SARS-CoV attaches to the ACE-2 on the cell membrane and enters through endocytosis [2].
DRUG INFORMATION:
Since SARS is a coronavirus in human genes, antiviral drugs have been tested for its effects on the reception of the SARS-CoV. One of the antiviral medicines that show of cytopathic effect is Ribavirin [4,7]. Ribavirin is a drug synthesized in 1970 at ICN Pharmaceuticals, Inc.; it can’t be found in nature. As an influenza treatment, ribavirin failed to pass through human trials due to mixed results [1]. It was originally meant to treat HIV, but proved to have been ineffective towards the disease. Ribavirin was not designed to target ACE-2 since ACE-2 was only discovered a few years after the 2003 pandemic, but the drug was designed to target receptors that function similar to ACE-2. Formula: C8H12N4O5MW = 244.206 g/mol. International CAS number: 36791-04-5It was also previously called tribavarin and RTCA.
Fig 3. Schematic structure of Ribavirin (C8H12N4O5); inhibits SARS-CoV from attaching by occupying the receptor first [6].
The Ribavirin structure shown above is what attaches to the receptor to block the SARS-CoV from entering the cell. There are three methods that this drug can be taken: tablet, aerosol inhilation, or liquid solution. Different pharmaceutical companies sell each form under a different brand name. The liquid form of ribavirin is under Rebetol; the pills are made by Copegus; the powdered aerosol inhalation form was sold under Virazole. Virazole is patented as a treatment for RSV (respiratory syncytial virus), and ribavirin is patented as a pairing for an interferon drug to inhibit binding of Hepatitis C in cells.
Fig. 4 Molecular model of Ribavirin. Carbon is in grey, hydrogen is white, and nitrogen and oxygen are blue and red, respectively [5].
Some of the side effects of taking ribavirin are as follows:
diarrhea
vomiting
dry mouth
hair loss.
There are also cases that result in even more serious side effects:
yellowing of the skin and eyes
bloody stools, depression
anemia.
Children who take ribavirin may experience weight gain and slow growth [8]. The Virazole and Copegus forms of ribavirin underwent clinical trials as a form of antiviral treatment for Hepatitis C, mainly paired with an interferon medication Pegasys. Many of these trials are still recruiting, quite a few are active, and plenty of the trials are actually complete and have results. However, no trials have been done that directly targets the SARS-CoV for ribavirin. Ribavirin is a drug that is directed towards different diseases (RSV and HepC), but the way it functions as an antiviral inhibitor mimics the effect that scientists are trying to achieve: stop the binding of SARS-CoV to the cell receptors. There is no proven data that shows that ribavirin is an effective drug against SARS, so despite physicians’ use of this drug back in 2003, ribavirin is not a proven treatment against SARS without the proper clinical trials. Alternative drugs to ribavirin have been used during the 2003 outbreak in Hong Kong. Lopinavir and ritonavir are protease inhibitors that are administered together since lopinavir itself is not an antiviral drug. These two were combined with ribavirin and steroids, which showed more improvement in health of SARS patients compared to only administering ribavirin and steroids together [9].
REFERENCES
[1] Franciscus, A. A Brief History of Hepatitis C. HCSP Fact Sheet, January 2006, pp 1-3.
[2] Kuba, K.; Imau, Y.; Ohto-Nakanishi, T.; Penninger, J. M., Trilogy of ACE2: A peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacology & Therapeutics 2010, 128, (1), 119-28.
[3] Nordqvist, C. What is SARS? What are the symptoms of SARS? Medical News Today. February 2013.
[4] Saijo, M.; Morikawa, S.; Fukushi, S.; Mizutani, T.; Hasegawa, H.; Nagata, N.; Iwata, N.; Kurane, I., Inhibitory effect of mizoribine and ribavirin on the replication of severe acute respiratory syndrome (SARS)-associated coronavirus. Antiviral Research 2005, 66, (2-3), 159-63.
[6] SciFinder Scholar, version 2014; Chemical Abstracts Service: Columbus, OH, 2014; RN 36791-04-5 (accessed February 1, 2014).
[7] Tan, E. L. C.; Ooi, E. E.; Lin, C.; Tan, H. C.; Ling, A. E.; Lim, B.; Stanton, L. W., Inhibition of SARS Coronavirus Infection In Vitro with Clinically Approved Antiviral Drugs. Emerging Infectious Diseases 2004, 10, (4), 581-6.
[9] Yu, W. C.; Hui, D. S. C.; Chan-Yeung, M., Antiviral agents and corticosteroids in the treatment of severe acute respiratory syndrome (SARS). Thorax 2004, 59, 643-45.
DISEASE/DRUG OF INTEREST:
SARS (Severe Acute Respiratory Syndrome)MOTIVATION AND BACKGROUND:
The SARS disease originated from the Guangdong Province of southern China where a farmer first showed the symptoms of SARS in 2002 but was not diagnosed definitively in the hospital. This viral disease did not get diagnosed until 2003 when a physician had a patient that traveled from Guangdong Province, Hong Kong, and Hanoi Vietnam. He and the patient died from the illness soon after [3]. The infected individuals came in contact with other people, which mitigated the spread of the disease to about thirty-seven countries in total, mostly in Asian countries such as Taiwan, Philippines, and Vietnam, but also in North America and some European countries. These cases were proven to have come from individuals who flew in from China, Hong Kong, or other countries where the disease was present.
The death toll of SARS was greater with adults the age of 65 and over most likely due to their lowered immune system. It has numerous symptoms, mainly known to be coughing, difficulty breathing, greater than 100.4-degree Fahrenheit fever, and other respiratory problems.
The more common symptoms resemble that of the flu:
- chills
- fever
- headache
- muscle ache.
Most patients also developed pneumonia after one week of infection [6]. Although not often, there are known to have been symptoms of diarrhea, nausea, vomiting, and sore throat that come up in some cases. The more severe instances have led patients to respiratory, liver and even heart failure [3].Reported cases of SARS have decreased greatly after the 2003 pandemic mainly because of the intense screening and protocols taken to contain its spread. Tests and planned treatments are available with the small number of cases that have risen these past decade. Even though SARS has infected less and less people in the past few years, an outbreak is still possible in the future, so preparation and prevention are still being done to this day.
TARGET INFORMATION:
There is no specific treatment or vaccine for the SARS virus, but studies have shown that the virus attaches to a receptor on the cell called angiotensin-converting enzyme 2 (ACE-2). This receptor is expressed mainly in the heart, kidneys, lungs, and gastrointestinal tract, which also happens to be where the SARS-CoV is found in infected patients. ACE-2 is a type I transmembrane glycoprotein made up of 805 amino acids [2]. Its molecular weight is unknown.
ACE-2 is a multifactorial enzyme that is known to be a protective component of the major organs in the body. In a normal cell, ACE-2 is a counter-regulator of its carboxylase homolog ACE, which increases blood pressure by constricting blood vessels. It also serves as an absorber of amino acids in the kidney and gut. At the same time, it is known to increase the effects and presence of the SARS-CoV by tenfold [2].
DRUG INFORMATION:
Since SARS is a coronavirus in human genes, antiviral drugs have been tested for its effects on the reception of the SARS-CoV. One of the antiviral medicines that show of cytopathic effect is Ribavirin [4,7]. Ribavirin is a drug synthesized in 1970 at ICN Pharmaceuticals, Inc.; it can’t be found in nature. As an influenza treatment, ribavirin failed to pass through human trials due to mixed results [1]. It was originally meant to treat HIV, but proved to have been ineffective towards the disease. Ribavirin was not designed to target ACE-2 since ACE-2 was only discovered a few years after the 2003 pandemic, but the drug was designed to target receptors that function similar to ACE-2.
Formula: C8H12N4O5MW = 244.206 g/mol. International CAS number: 36791-04-5It was also previously called tribavarin and RTCA.
The Ribavirin structure shown above is what attaches to the receptor to block the SARS-CoV from entering the cell.
There are three methods that this drug can be taken: tablet, aerosol inhilation, or liquid solution. Different pharmaceutical companies sell each form under a different brand name. The liquid form of ribavirin is under Rebetol; the pills are made by Copegus; the powdered aerosol inhalation form was sold under Virazole. Virazole is patented as a treatment for RSV (respiratory syncytial virus), and ribavirin is patented as a pairing for an interferon drug to inhibit binding of Hepatitis C in cells.
Some of the side effects of taking ribavirin are as follows:
There are also cases that result in even more serious side effects:
Children who take ribavirin may experience weight gain and slow growth [8].
The Virazole and Copegus forms of ribavirin underwent clinical trials as a form of antiviral treatment for Hepatitis C, mainly paired with an interferon medication Pegasys. Many of these trials are still recruiting, quite a few are active, and plenty of the trials are actually complete and have results. However, no trials have been done that directly targets the SARS-CoV for ribavirin. Ribavirin is a drug that is directed towards different diseases (RSV and HepC), but the way it functions as an antiviral inhibitor mimics the effect that scientists are trying to achieve: stop the binding of SARS-CoV to the cell receptors.
There is no proven data that shows that ribavirin is an effective drug against SARS, so despite physicians’ use of this drug back in 2003, ribavirin is not a proven treatment against SARS without the proper clinical trials. Alternative drugs to ribavirin have been used during the 2003 outbreak in Hong Kong. Lopinavir and ritonavir are protease inhibitors that are administered together since lopinavir itself is not an antiviral drug. These two were combined with ribavirin and steroids, which showed more improvement in health of SARS patients compared to only administering ribavirin and steroids together [9].
REFERENCES
[1] Franciscus, A. A Brief History of Hepatitis C. HCSP Fact Sheet, January 2006, pp 1-3.
[2] Kuba, K.; Imau, Y.; Ohto-Nakanishi, T.; Penninger, J. M., Trilogy of ACE2: A peptidase in the renin-angiotensin system, a SARS receptor, and a partner for amino acid transporters. Pharmacology & Therapeutics 2010, 128, (1), 119-28.
[3] Nordqvist, C. What is SARS? What are the symptoms of SARS? Medical News Today. February 2013.
[4] Saijo, M.; Morikawa, S.; Fukushi, S.; Mizutani, T.; Hasegawa, H.; Nagata, N.; Iwata, N.; Kurane, I., Inhibitory effect of mizoribine and ribavirin on the replication of severe acute respiratory syndrome (SARS)-associated coronavirus. Antiviral Research 2005, 66, (2-3), 159-63.
[5] Science Photo Library. Ribavirin Drug Molecule. http://www.sciencephoto.com/media/449793/view (accessed Feb 17, 2014).
[6] SciFinder Scholar, version 2014; Chemical Abstracts Service: Columbus, OH, 2014; RN 36791-04-5 (accessed February 1, 2014).
[7] Tan, E. L. C.; Ooi, E. E.; Lin, C.; Tan, H. C.; Ling, A. E.; Lim, B.; Stanton, L. W., Inhibition of SARS Coronavirus Infection In Vitro with Clinically Approved Antiviral Drugs. Emerging Infectious Diseases 2004, 10, (4), 581-6.
[8] Wellness. SARS: Prevention and Treatment. http://www.wellness.com/reference/conditions/sars/prevention-and-treatment (accessed Feb 1, 2014).
[9] Yu, W. C.; Hui, D. S. C.; Chan-Yeung, M., Antiviral agents and corticosteroids in the treatment of severe acute respiratory syndrome (SARS). Thorax 2004, 59, 643-45.